Vaccinations that are based on the use of live, attenuated infectious agents (i.e. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been postulated, and in some cases shown, to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of a secondary infectious challenge. However, it is currently unknown 1) whether the protein antigen contained within a subunit vaccination also persists in the host for extended periods of time, 2) if so, by what basis this persistence is established and maintained, and 3) whether this persisting antigen contributes to or detracts from the maintenance of protective immune memory in the host. These are critical parameters to comprehend and control as we consider future vaccine design and development. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. In the process, we recently observed that our subunit-based vaccine approach can also result in long term persistence of antigen in the host. Based on these preliminary data, we hypothesize that the persistence of antigen derived from non-infectious, subunit vaccination results from an interaction and communication between DCs and LECs. Our data predict that this communication is dependent upon innate receptor activation of either the DCs or the LECs or both. We further hypothesize that methods of vaccination that enhance antigen persistence will promote protective immune memory and that elimination of persisting antigen will have a deleterious effect on the maintenance of effector and effector memory cells capable of mediating rapid clearance of viral or bacterial agents. We will test these hypotheses by examining the mechanisms by which protein antigen persists in a host following a subunit vaccination, and determining the immunologic impact of antigen persistence on the development and maintenance of protective immunity against infectious agents. PUBLIC HEALTH RELEVANCE: Vaccinations that are based on the use of live, attenuated infectious agents (ie. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been postulated, and in some cases shown, to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of a secondary infectious challenge. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. In the process, we recently observed that our subunit-based vaccine approach can also result in long term persistence of antigen in the host. This project will elucidate the mechanisms by which protein antigen persists in a host following a subunit vaccination, and determine the immunologic impact of that antigen persistence on the development and maintenance of protective immunity against infectious agents.